DESCRIPTION: The objective of this renewal program is to develop methodology for the total synthesis of a variety of naturally occurring alkaloids. It is indicated that a primary target of this research is sarain A, a highly unusual polycyclic compound isolated from the marine sponge Reniera sarai. The principal investigator reports that the tricyclic core of this unique alkaloid has now been synthesized by a route involving an intramolecular (3+2)- dipolar cycloaddition of an azomethine ylid, and an allylsilane/N-sulfonyliminium ion cyclization as key steps and that completion of the synthesis will now require annulation of the two macrocyclic rings of the natural product onto an existing tricyclic intermediate. It is indicated that a general route to total synthesis of the Securinega class of plant alkaloids is proposed and that the strategy utilizes commercially available, optically pure 4-hydroxyproline as a source of the alkaloid B-ring and the absolute stereochemistry at C-7. It is noted that to date, an advanced B,C-ring bicyclic intermediate has been prepared via a sequence involving an intramolecular SmI2-induced ketonitrile cyclization and the application of a new method for amide oxidation. The principal investigator states that this pivotal compound will now be utilized in total syntheses of (-)-norsecurinine, securinine, allosecurinine, and phyllanthine. The final operation in each synthesis is to be a transition metal-catalyzed Kharasch atom transfer cyclization of a dichloroacetate ester or related derivative, followed by a double elimination to generate the diene lactone system of the alkaloids. The principal investigator notes that the amide oxidation methodology developed for application to the Securinega alkaloid project is to be explored in more detail and extended in its scope. He states that a double oxidation will be investigated and this process will be applied to the beta-glucosidase and mannosidase inhibiting alkaloid 2(R)-,5(R)- bis(hydroxymethyl)-3(R),4(R)- dihydroxypyrrolidine. Finally, methodology is to be developed for the synthesis of bifunctional allyl vinyl silanes and the use of these synthons as annulating reagents is to be investigated. Application of this chemistry to the synthesis of anatoxin-a is to be developed.